In real life, various complications often disguise a basic Mendelian pattern. Figures 1–6 illustrate several common complications.
Fig1. Complications to the basic Mendelian patterns (1): variable expression. Different affected family members show different features of type 1 Waardenburg syndrome, an autosomal dominant trait (OMIM #193500), although they all have the same mutation in the PAX3 gene.
Fig2. Complications to the basic Mendelian patterns (2): nonpenetrance. The pedigree shows transmission of an autosomal dominant condition. Individual II2 (arrowed) evidently carries the gene for the condition but does not show symptoms. Other unaffected family members, such as II3 , III1 , III7 , IV1 , or IV2 , might also be non penetrant gene carriers.
Fig3. Age-of-onset curves for Huntington disease. Curve A shows the probability that an individual carrying the disease allele will have developed symptoms by a given age. Curve B shows the risk at a given age that an asymptomatic person who has an affected parent nevertheless carries the disease allele. (From Harper PS [2010] Practical Genetic Counselling, 7th edn. With permission from CRC Press.)
Fig4. Complications to the basic Mendelian patterns (3): a male-lethal X-linked condition. In this family with X-linked dominant incontinentia pigmenti (OMIM #308300), affected males abort spontaneously (small squares).
Fig5. Complications to the basic Mendelian patterns (4): an X-linked recessive pedigree with inbreeding. There is an affected female and apparent male-to-male transmission. The pedigree could easily be misinterpreted as showing an autosomal recessive condition.
Fig6. Complications to the basic Mendelian patterns (5): a common recessive condition giving an apparently dominant pedigree. If a recessive trait is sufficiently common that unrelated people marrying into the family often carry it, the pedigree may misleadingly resemble that of a dominant trait. The condition in the figure is blood group O.
Many conditions show variable expression
Variable expression describes the frequent observation that affected individuals within a pedigree may show different degrees of severity or different features of the condition. Variable expression is especially a feature of dominant conditions. Figure1 shows an example from a family with the autosomal dominant condition Waardenburg syndrome (OMIM #193500). As a general rule, recessive conditions are less variable than dominant ones, probably because the phenotype of a heterozygote involves a balance between the effects of the two alleles, so that the outcome is likely to be more sensitive to outside influence than the phenotype of a homozygote. Careful examination of people with a recessive condition will nevertheless often also show some degree of variability.
These complications are much more conspicuous in humans than in experimental organisms. Laboratory animals and crop plants are far more genetically uniform than humans, and live in much more constant environments. What we see in human genetics is typical of a natural mammalian population. Nevertheless, mouse geneticists are familiar with the way in which the expression of a mutant gene can change when it is bred onto a different genetic background—an important consideration when studying mouse models of human diseases.
Nonpenetrance: a dominant condition may fail to manifest itself
Nonpenetrance is the extreme of variable expression. The penetrance of a character, for a given genotype, is the probability that a person who has the genotype will mani fest the character. By definition, a dominant character is manifested in a heterozygous person, and so should show 100% penetrance. Nevertheless, many human characters, although generally showing dominant inheritance, occasionally skip a generation. In Figure 2, II2 has an affected parent and an affected child, and almost certainly carries the mutant gene, but is phenotypically normal. This would be described as a case of nonpenetrance.
There is no mystery about nonpenetrance—indeed, 100% penetrance is the more sur prising phenomenon. Very often the presence or absence of a character depends, in the main and in normal circumstances, on the genotype at one locus, but an unusual genetic background, a particular lifestyle, or maybe just chance means that the occasional per son may fail to manifest the character. Nonpenetrance is a major pitfall in genetic counseling. It would be an unwise counselor who, knowing that the condition in Figure 2 was dominant and seeing that III7 was free of signs, told her that she had no risk of having affected children. One of the jobs of genetic counselors is to know the usual degree of penetrance of each dominant condition.
Age-related penetrance in late-onset diseases
A particularly important case of reduced penetrance is seen with late-onset diseases. Genetic conditions are not necessarily congenital (present at birth). The genotype is fixed at conception, but the phenotype may not manifest until adult life. In such cases the penetrance is age related. Huntington disease is a well-known example (Figure3).
Delayed onset might be caused by the slow accumulation of a noxious substance, by incremental tissue death, or by an inability to repair some form of environmental dam age. Hereditary cancers are caused by a chance second mutation affecting a cell of a person who already carries one mutation in a tumor suppressor gene in every cell. That second mutation could occur at any time, and so the risk of having acquired it is cumulative and increases through life. Depending on the disease, the penetrance may become 100% if the person lives long enough, or there may be people who carry the gene but who will never develop symptoms no matter how long they live. Age of-onset curves such as those in Figure 3 are important tools in genetic counseling, because they enable the geneticist to estimate the chance that an at-risk but asymptomatic person will subsequently develop the disease.
Multigeneration pedigrees often give the appearance of anticipation Anticipation
describes the tendency of some conditions to become more severe, or have earlier onset, in successive generations. true anticipation is a hallmark of conditions caused by a very special genetic mechanism, dynamic mutation. But when a dominant condition shows random variations in severity, this can easily produce a false impression of anticipation. Mildly affected parents who have a severely affected child will bring it to the clinic. On the other hand, severely affected people may never become parents, or if they do and have a mildly affected child, they might not see any reason to bring it to clinical attention. Thus the clinician’s experience is usually of mildly affected parents having severely affected children, and not the reverse. There is a systematic bias of ascertainment that mimics true anticipation. Claims of anticipation without evidence of a dynamic mutation should be treated with great caution. To be credible, a claim of anticipation requires careful statistical backing or direct molecular evidence, not just clinical impression.
Male lethality may complicate X-linked pedigrees
For some X-linked dominant conditions, absence of the normal allele is lethal before birth. Thus affected males are not born, and we see a condition that affects only females, who pass it on to half their daughters but none of their sons. If the family were large enough, one might notice that there are only half as many boys as girls, and a history of miscarriages (because the 50% of males who inherited the mutant allele miscarry before birth). An example is incontinentia pigmenti (Figure 4; linear skin defects following defined patterns known as Blaschko’s lines, often accompanied by neurological or skeletal problems; OMIM #308300). Rett syndrome (OMIM #312750) is another case (see Section 10.3). Affected girls are normal at birth and develop normally for the first year or two, but then stop developing, and eventually regress, losing speech and other abilities that they acquired in early life. In males, Rett syndrome is usually lethal before birth, but rare survivors have a severe neonatal encephalopathy. Until the causative gene was cloned, it was not recognized that these males had the same gene defect as females with classical Rett syndrome.
Inbreeding can complicate pedigree interpretation
The absence of male-to-male transmission is a hallmark of X-linked pedigree patterns— but if an affected man marries a carrier woman, he may have an affected son. Naturally this is most likely to happen as a result of inbreeding in a family in which the condition is segregating. Such matings can also produce homozygous affected females. Figure 5 shows an example.
Metabolic interference could result in heterozygotes for a condition being affected while both homozygotes are unaffected
Metabolic interference was suggested by WG Johnson (1980) (PMID 6770678) as a hypo thetical mechanism by which two alleles at a locus, each in itself fully functional, could conflict so as to produce a phenotype in heterozygotes, while both homozygotes would be unaffected. Craniofrontonasal syndrome (OMIM #304110) has often been cited as a possible example. It is an X-linked condition in which males carrying the mutant gene are very mildly affected compared to heterozygous females. The causative mutation is in the EFNB1 (Ephrin B1) gene at Xp13. Ephrin B1 is involved in defining tissue boundaries. It appears that it is largely dispensable, because males with null mutations have mini mal disease signs. Heterozygous females have problems because of X-inactivation. As discussed in Section 10.4, because of X-inactivation a heterozygous female has clones of ephrin-expressing cells mingled with clones of cells expressing no ephrin. The problems arise when cells from positive and negative clones try to form a boundary. Thus, this is not a true example of metabolic interference as conceived by Johnson; it is, however, an example of cellular interference—a conclusion strengthened by the observation that males mosaic for loss-of-function mutations are more severely affected than males with constitutional mutations. It is not clear that any good example of simple metabolic interference as proposed by Johnson has been identified in humans.
The classic Mendelian patterns are best seen with rare conditions
If a recessive trait is common in a population, there is a good chance that it may be brought into the pedigree independently by two or more people. A common recessive character such as blood group O may be seen in successive generations because of repeated matings of group O people with heterozygotes. This produces a pattern resembling dominant inheritance (Figure 6). The classic Mendelian pedigree patterns are best seen with rare conditions, where there is little chance that somebody who marries into the family might coincidentally also carry the disease mutation that is segregating in the family.
All these complications to the basic Mendelian patterns reinforce the fact that only a very small fraction of all variants do determine a phenotype directly and with high penetrance. It is a failing in the way genetics is taught that students all too often imagine that clean Mendelian inheritance is the norm for any genetic character, and that any greater complexity in the mode of inheritance is somehow exceptional, abnormal, and best ignored as long as possible. Genes are always Mendelian, but phenotypes are not. Reduced penetrance and variable expression show the effect of the genotypes at other loci (“modifier genes”), plus nongenetic factors and maybe simple chance. As the role of these other factors increases, there comes a point where it is no longer useful to describe a condition as Mendelian. all genetic determination lies along a spectrum, ranging from fully penetrant monogenic characters through to polygenic, where the phenotype is the result of the combined effects of variants at many loci, no one of which has a major effect by itself.
Identifying the mode of inheritance and estimating recurrence risks for Mendelian conditions is as much an art as a science. Increasingly nowadays molecular testing identifies causative mutations and removes the necessity of interpreting the pedigree, but where this still has to be done, the answer is often not completely clear. Families are often too small to make the pattern unambiguous, variable expression leads to uncertainty whether an individual is affected or not, and nonpenetrance obscures the transmission of a disease allele. This is not a problem for students sitting exams—the examiner will have made sure that there is one correct answer—but in real life it would be wise not to attempt amateur genetic counseling. Leave it to trained (and insured) professionals!
